The present invention relates to novel benzimidazole compounds, pharmaceutical compositions containing these compounds, methods of treating therewith, and to method of preparing such benzimidazole compounds. The novel compounds of the invention are useful in the treatment of central nervous system diseases and disorders, which are responsive to modulation of the GABAA receptor complex, such as for example anxiety, sleep disorders, anaestesia, memory disorders, and epilepsia or other convulsive disorders.
GABAA receptors for xcex3-aminobutyric acid (GABA) are the most abundant inhibitory receptors in the mammalian brain. The GABAA receptors are structurally constituted as macromolecular heteropentameric assemblies (combinations of xcex1, xcex2, and xcex3/xcex4 protein subunits). Several subtypes of such GABAA receptors have been described by techniques of modern molecular biology.
Each GABAA receptor complex comprises a chloride ion channel that controls chloride flux across the neuronal membrane, and multiple recognition sites for small modulatory molecules such as benzodiazepines, barbiturates, picrotoxin, and certain steroids. When GABA interacts with its receptor, the ion channel is opened, chloride influx is enhanced, the membrane is hyperpolarized and the cell becomes less responsive to excitatory stimuli. This GABA induced ion current can be regulated by diverse agents, including agents that interact with the benzodiazepine receptor or recognition site.
Agents that bind or interact with the modulatory sites on the GABAA receptor complex, such as for example the benzodiazepine receptor, can have either enhancing effect on the action of GABA, i.e. a positive modulatory effect of the receptor (agonists, partial agonists), an attenuating effect on the action of GABA, i.e. negative modulation of the receptor (inverse agonists, partial inverse agonists), or they can block the effect of both agonists and inverse agonists by competitive block (antagonists or ligands without intrinsic activity).
Agonists generally produce muscle relaxant, hypnotic, sedative, anxiolytic, and/or anticonvulsant effects, while inverse agonists produce proconvulsant, anti-inebriant, and anxiogenic effects. Compounds with anxiolytic effects but without or with reduced muscle relaxant, hypnotic and sedative effects are characterised as partial agonists. Partial inverse agonists are considered to be useful as cognition enhancers.
Numerous compounds belonging to different chemical series of compounds having affinity for the benzodiazepine receptors have been synthesized during the last three decades. However, although the benzodiazepine receptor sites are still considered as very attractive biological sites for interfering with the CNS to treat various disorders and diseases, then nearly all previously synthesized compounds acting at these receptor sites have failed during clinical development because of unacceptable side effects.
It is an object of the present invention to provide novel benzimidazole derivatives and pharmaceutically acceptable acid addition salts thereof, which are useful in the treatment of central nervous system disorders, diseases or ailments, which are responsive to the modulation of the GABAA receptor complex, and in particular the positive modulation of the GABAA receptor complex, and having a favorable pharmacodynamic and pharmacokinetic behavior.
Accordingly, the invention provides a chemical compound represented by the general formula (I): 
in which formula (I),
o is 0, 1, 2 or 3;
R1 represents an alkyl group, a phenyl group, or a monocyclic heterocyclic group, which groups may be substituted one or more times with substituents selected from alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, halogen, trifluoromethyl, cyano, amino, and nitro;
or R1 represents a cyano group, or a group of the formula -alkyl-CO2R2, alkenyl-CO2R2, xe2x80x94COxe2x80x94R2, xe2x80x94CO2(CH2)mR2, or xe2x80x94C(R3)xe2x95x90Nxe2x80x94OR2, in which formulas
m is 0, 1, 2 or 3;
R2 and R3 independently represents hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, a 5- or 6-membered heterocyclic group, which 5- or 6-membered heterocyclic group may optionally be substituted one or more times with substituents selected from alkyl, hydroxy, alkoxy, halogen, trifluoromethyl, cyano, amino, or nitro;
or R2 and R3 may independently represent a group of the formula xe2x80x94(CH2)qxe2x80x94NR4R5, xe2x80x94(CH2)qxe2x80x94CON(R4R5), xe2x80x94(CH2)qxe2x80x94CO2R4, or -alkyl-CO2R4, in which formulas
R4 and R5 independently represent hydrogen or alkyl; and
q is 0, 1, 2 or 3;
R11 represents a group of the general formula xe2x80x94CO2xe2x80x94R9, wherein
R9 represents hydrogen or alkyl, which alkyl may optionally be substituted with a 5- or 6-membered heterocyclic group, which 5- or 6-membered heterocyclic group may optionally be substituted one or more times with substituents selected from alkyl, hydroxy, alkoxy, halogen, trifluoromethyl, cyano, amino, or nitro;
or R9 may be a 5- or 6-membered heterocyclic group, which 5- or 6-membered heterocyclic group may optionally be substituted one or more times with substituents selected from alkyl, hydroxy, alkoxy, halogen, trifluoromethyl, cyano, amino, or nitro; or R9 represent a group of the general formula -alkyl-N(R10R12), in which formula
R10 and R12 independently represent hydrogen or alkyl;
or R11 represents a group of general formula (II): 
in which formula (II),
n is 0, 1, 2, or 3;
Rxe2x80x2 and Rxe2x80x3 each independently represents hydrogen or alkyl;
or Rxe2x80x2 and Rxe2x80x3 together with the N atom to which they are attached form a 5- to 7-membered heterocyclic ring, which heterocyclic ring may optionally comprise as a ring member, one oxygen atom, and/or one additional nitrogen atom, and/or a xe2x80x94CHxe2x95x90CHxe2x80x94 chain;
and in which formula the 5- to 7-membered heterocyclic ring formed by Rxe2x80x2 and Rxe2x80x3 may optionally be substituted one ore more times with a group of the formula xe2x80x94(CH2)pX, wherein
p is 0, 1, 2 or 3;
X represents hydrogen, hydroxy, alkyl or alkenyl, which alkyl and alkenyl may optionally be substituted one or more times with a group of the formula xe2x80x94CO2R6;
or X represents a group of the formula xe2x80x94COxe2x80x94R6, xe2x80x94CO2xe2x80x94R6, xe2x80x94CONxe2x80x94R6R7, or xe2x80x94COOxe2x80x94R6xe2x80x94NR7R8, in which formulas
R6, R7 and R8 independently represents hydrogen or alkyl;
or R11 may represent a group of the general formula (III): 
in which formula (III),
n is 0, 1, 2 or 3;
Rxe2x80x2 is hydrogen or alkyl;
Rxe2x80x2xe2x80x3 and Rxe2x80x3xe2x80x3 together with the atoms to which they are attached form a 5- to 7-membered heterocyclic ring, which heterocyclic ring may optionally comprise as a ring member, one oxygen atom, and/or one additional nitrogen atom, and/or a xe2x80x94CHxe2x95x90CHxe2x80x94 chain;
and in which formula the 5- to 7-membered heterocyclic ring formed by Rxe2x80x2xe2x80x3 and Rxe2x80x3xe2x80x3 may optionally be substituted one ore more times with a group of the formula xe2x80x94(CH2)pX, wherein
p is 0, 1, 2 or 3;
X represents hydrogen, hydroxy, alkyl or alkenyl, which alkyl and alkenyl may optionally be substituted one or more times with a group of the formula xe2x80x94CO2R6;
or X represents a group of the formula xe2x80x94COxe2x80x94R6, xe2x80x94CO2xe2x80x94R6, xe2x80x94CONxe2x80x94R6R7, or xe2x80x94COOxe2x80x94R6xe2x80x94NR7R8, in which formulas
R6, R7 and R8 independently represents hydrogen or alkyl;
or a pharmaceutically acceptable salt thereof or an oxide thereof.
In another aspect, the invention provides pharmaceutical compositions comprising the novel benzimidazole compounds of the invention.
Still another object of the present invention is to provide novel methods of treatment using the novel benzimidazole compounds of the invention.
A further object of the present invention is to provide a method of preparing the novel pharmaceutical compositions of the invention.
Additional objects will be obvious from the following description, and others will be obvious to a person skilled in the art.
Benzimidazole Derivatives
In its first aspect the invention provides novel benzimidazole derivatives. The chemical compounds of the invention may be characterized by the following general formula (I): 
in which formula (I),
o is 0, 1, 2 or 3;
R1 represents an alkyl group, a phenyl group, or a monocyclic heterocyclic group, which groups may be substituted one or more times with substituents selected from alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, halogen, trifluoromethyl, cyano, amino, and nitro;
or R1 represents a cyano group, or a group of the formula -alkyl-CO2R2, alkenyl-CO2R2, xe2x80x94COxe2x80x94R2, xe2x80x94CO2(CH2)mR2, or xe2x80x94C(R3)xe2x95x90Nxe2x80x94OR2, in which formulas
m is 0, 1, 2 or 3;
R2 and R3 independently represents hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, a 5- or 6-membered heterocyclic group, which 5- or 6-membered heterocyclic group may optionally be substituted one or more times with substituents selected from alkyl, hydroxy, alkoxy, halogen, trifluoromethyl, cyano, amino, or nitro;
or R2 and R3 may independently represent a group of the formula xe2x80x94(CH2)qxe2x80x94NR4R5, xe2x80x94(CH2)qxe2x80x94CON(R4R5), xe2x80x94(CH2)qxe2x80x94CO2R4, or -alkyl-CO2R4, in which formulas
R4 and R5 independently represent hydrogen or alkyl; and
q is 0, 1, 2 or 3;
R11 represents a group of the general formula xe2x80x94CO2xe2x80x94R9, wherein
R9 represents hydrogen or alkyl, which alkyl may optionally be substituted with a 5- or 6-membered heterocyclic group, which 5- or 6-membered heterocyclic group may optionally be substituted one or more times with substituents selected from alkyl, hydroxy, alkoxy, halogen, trifluoromethyl, cyano, amino, or nitro;
or R9 may be a 5- or 6-membered heterocyclic group, which 5- or 6-membered heterocyclic group may optionally be substituted one or more times with substituents selected from alkyl, hydroxy, alkoxy, halogen, trifluoromethyl, cyano, amino, or nitro;
or R9 represent a group of the general formula -alkyl-N(R10R12), in which formula
R10 and R12 independently represent hydrogen or alkyl;
or R11 represents a group of general formula (II): 
in which formula (II),
n is 0, 1, 2, or 3;
Rxe2x80x2 and Rxe2x80x3 each independently represents hydrogen or alkyl;
or Rxe2x80x2 and Rxe2x80x3 together with the N atom to which they are attached form a 5- to 7-membered heterocyclic ring, which heterocyclic ring may optionally comprise as a ring member, one oxygen atom, and/or one additional nitrogen atom, and/or a xe2x80x94CHxe2x95x90CHxe2x80x94 chain; and in which formula the 5- to 7-membered heterocyclic ring formed by Rxe2x80x2 and Rxe2x80x3 may optionally be substituted one ore more times with a group of the formula xe2x80x94(CH2)pX, wherein
p is 0, 1, 2 or 3;
X represents hydrogen, hydroxy, alkyl or alkenyl, which alkyl and alkenyl may optionally be substituted one or more times with a group of the formula xe2x80x94CO2R6;
or X represents a group of the formula xe2x80x94COxe2x80x94R6, xe2x80x94CO2xe2x80x94R6, xe2x80x94CONxe2x80x94R6R7, or xe2x80x94COOxe2x80x94R6xe2x80x94NR7R8, in which formulas
R6, R7 and R8 independently represents hydrogen or alkyl;
or R11 may represent a group of the general formula (III): 
in which formula (III),
n is 0, 1, 2 or 3;
Rxe2x80x2 is hydrogen or alkyl;
Rxe2x80x2xe2x80x3 and Rxe2x80x3xe2x80x3 together with the atoms to which they are attached form a 5- to 7-membered heterocyclic ring, which heterocyclic ring may optionally comprise as a ring member, one oxygen atom, and/or one additional nitrogen atom, and/or a xe2x80x94CHxe2x95x90CHxe2x80x94 chain;
and in which formula the 5- to 7-membered heterocyclic ring formed by Rxe2x80x2xe2x80x3 and Rxe2x80x3xe2x80x3 may optionally be substituted one ore more times with a group of the formula xe2x80x94(CH2)pX, wherein
p is 0, 1, 2 or 3;
X represents hydrogen, hydroxy, alkyl or alkenyl, which alkyl and alkenyl may optionally be substituted one or more times with a group of the formula xe2x80x94CO2R6;
or X represents a group of the formula xe2x80x94COxe2x80x94R6, xe2x80x94CO2xe2x80x94R6, xe2x80x94CONxe2x80x94R6R7,
or xe2x80x94COOxe2x80x94R6xe2x80x94NR7R8, in which formulas
R6, R7 and R8 independently represents hydrogen or alkyl.
In a preferred embodiment, the chemical compound of the invention is characterized by the general formula (I) in wherein o is 0; and
R1 represents a C1-4-alkyl group, a cyano group, a phenyl group, a furanyl group, a tetrahydrofuranyl group, an isoxazolyl group, or an oxadiazolyl group;
or R1 represents a C1-4-alkenyl group substituted with CO2xe2x80x94C1-4-alkyl;
or R1 represents a group of the formula xe2x80x94CO2R2, in which formula
R2 represents hydrogen, a C1-4-alkyl group, or a xe2x80x94C3-5-cyclo-C1-4-alkyl group, a benzyl group, a picolyl group, a pyrrolidyl group, a pyrrolidyl-methyl group, or a pyridyl group, which groups may be substituted with a C1-3-alkyl group;
or R2 may represent a group of the formula xe2x80x94(CH2)pxe2x80x94NR4R5, or xe2x80x94(CH2)pxe2x80x94COxe2x80x94NR4R5, in which formulas
p is 0, 1, or 2;
R4 and R5 each independently represents hydrogen or a C1-4-alkyl group;
or R2 may represent a group of the formula xe2x80x94C(R3)xe2x95x90Nxe2x80x94OR4, in which formula
R3 and R4 each independently represents hydrogen or a C1-4-alkyl group;
or R1 represents a group of the formula xe2x80x94C(R3)xe2x95x90Nxe2x80x94OR4, in which formula
R3 represents hydrogen or a C1-4-alkyl group;
and R4 represents hydrogen, a C1-4-alkyl group, or a C1-4-alkyl-CO2xe2x80x94C1-4-alkyl group.
In a more preferred embodiment, the chemical compound of the invention is characterized by the general formula (I) in wherein o is 0; and
R1 is 3-furanyl, 3-tetrahydro-furanyl, 5-isoxazolyl, 3-cyclopropyl-1,2,4-oxadiazol-5-yl, xe2x80x94CHNOH, xe2x80x94C(CH3)NOH, xe2x80x94C(CH3)NOxe2x80x94CH3, xe2x80x94C(CH3)NOxe2x80x94C2H5, xe2x80x94C(CH3)NO-isopropyl, xe2x80x94C(CH3)NO-t-butyl, xe2x80x94C(CH3)NOxe2x80x94CH2CO2CH3, xe2x80x94C(CH3)NOxe2x80x94CH2CO2C2H5, xe2x80x94CHNOxe2x80x94C(CH3)2CO2CH3, xe2x80x94C(CH3)NOxe2x80x94C(CH3)2CO2CH3, xe2x80x94C(CH3)NOxe2x80x94C(CH3)2CO2C2H5, xe2x80x94C(CH3)2CO2CH5, xe2x80x94C(CH3)NOxe2x80x94C(CH3)2CO2C2H5, xe2x80x94CO2CH3, xe2x80x94CO2C2H5, xe2x80x94CO2CH(CH3)2, xe2x80x94CO2(CH2)2N(CH3)2, xe2x80x94CO2(CH2)2N(C2H5)2, xe2x80x94CO2xe2x80x94CH2-cyclopropyl, (N,N-diethyl-carboxamido)-methyl, 3-picolyl, or 1-methyl-2-pyrrolidyl-methyl.
In another preferred embodiment, the chemical compound of the invention is characterized by the general formula (I) in wherein o is 1, 2 or 3; and
R1 represents a phenyl group, or a group of the formula xe2x80x94CO2R4, in which formula
R4 represents hydrogen or a C1-4-alkyl group.
In a more preferred embodiment, the chemical compound of the invention is characterized by the general formula (I) in wherein o is 1, 2 or 3; and
R1 is xe2x80x94CO2CH3, xe2x80x94CO2C2H5, xe2x80x94CO2CH(CH3)2, xe2x80x94CO2CH2-cyclopropyl, xe2x80x94CHNOxe2x80x94CH3, xe2x80x94CHNOxe2x80x94C2H5, xe2x80x94CHNOxe2x80x94C3H7, xe2x80x94CHNOxe2x80x94 isopropyl, xe2x80x94C(CH3)NOxe2x80x94CH3, xe2x80x94C(CH3)NOxe2x80x94C2H5, xe2x80x94C(CH3)NOxe2x80x94C3H7, xe2x80x94C(CH3)NO-isopropyl, xe2x80x94C(CH3)NOxe2x80x94C4H9, xe2x80x94C(CH3)NO-tert. butyl, xe2x80x94CO2CH2N(CH3)2, xe2x80x94CO2CH2N(C2H5)2, 2(dimethyl-amino)ethyl, (N,N-diethyl-carboxamido)-methyl, or 3-picolyl.
In another preferred embodiment, the chemical compound of the invention is characterized by the general formula (I) in wherein
R11 represents a C1-4-alkyl-oxycarbonyl group, an amino-C1-4-alkyl-oxycarbonyl group, an Nxe2x80x94C1-4-alkyl-amino-C1-4-alkyl-oxycarbonyl group, an N,N-di-(C1-4-alkyl)-amino-C1-4-alkyl-oxycarbonyl group, a piperidinyl group, an oxycarbonyl-piperidinyl group, a pyrrolidinyl group, a pyrrolidinyl-C1-4-alkyl group, a piperazinyl group, a morpholinyl group, a homopiperazinyl group, a pyridyl group, a tetrahydropyridyl group, a picolyl group, a oxycarbonyl-picolyl group, which groups may optionally be substituted one or more times with substituents selected from C1-4-alkyl, C1-4-alkyl-oxy, C1-4-alkyl-oxycarbonyl, C1-4-alkyl-oxycarbonyl-C1-4-alkyl, C1-4-alkenyl-oxycarbonyl-C1-4-alkyl, C1-4-alkenyl-(oxycarbonyl-C1-4-alkyl)2, acetyl, hydroxy-C1-4-alkyl, carboxamido, Nxe2x80x94C1-4-alkyl-carboxamido-C1-4-alkyl, or N,N-di-C1-4-alkyl-carboxamido-C1-4-alkyl.
In a more preferred embodiment, the chemical compound of the invention is characterized by the general formula (I) in wherein
R11 is 1-piperidinyl, 1-pyrrolidinyl, 4-methyl-1-piperazinyl, 1-methyl-3-piperidinyl, (1-methyl-4-piperidinyl)oxycarbonyl, (1-methyl-3-piperidinyl)oxycarbonyl, 2-picolyl-oxycarbonyl, 3-picolyl-oxycarbonyl, 4-morpholinyl, 1-acetyl-4-piperazinyl, 4-(2-hydroxyethyl)piperazin-1-yl, (1-pyrrolidinyl)methyl, 4-methylhomopiperazin-1-yl, 1-methyl-1,2,3,6-tetrahydropyrid-5-yl, 4-(N,N-diethyl-carboxamidomethyl)-piperazin-1-yl, 4-(N,N-dimethyl-carboxamidomethyl)-piperazin-1-yl, 4-(methoxycarbonylmethyl)-1-piperazinyl, 4-(ethoxycarbonylmethyl)-1-piperazinyl, 4-(t-butoxycarbonylmethyl)-1-piperazinyl, 4-(diethylcarboxamido-methyl)piperazin-1-yl, 4-(2,2-bis(ethoxycarbonyl)-ethenyl)piperazin-1-yl, 4-(2-methoxycarbonyl-ethenyl)piperazin-1-yl, methoxycarbonyl, ethoxycarbonyl, 2-amino-ethoxycarbonyl, 2-(N-methylamino)ethoxycarbonyl, or 2-(N,N-dimethylamino)ethoxycarbonyl. In a most preferred embodiment the chemical compound of the invention is
5-Cyano-1-(3-(1-piperidyl)phenyl)benzimidazole (compound 3a);
5-Cyano-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole (compound 3a2);
5-Cyano-1-(3-(4-methyl-1-piperazinyl)phenyl)benzimidazole (compound 3a3);
5-Cyano-1-(3-(1-methyl-3-piperidinyl)phenyl)benzimidazole (compound 3a4);
5-Cyano-1-(3-(4-morfolinyl)phenyl benzimidazole (compound 3a5);
5-Formyl-1-(3-(1-piperidinyl)phenyl)benzimidazole oxime (compound 3b1);
5-Formyl-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole oxime (compound 3b2):
5-Formyl-1-(3-(4-methyl-1-piperazinyl)phenyl)benzimidazole oxime (compound 3b3);
5-Formyl-1-(3-(1-methyl-3-piperidinyl)phenyl)benzimidazole oxime (compound 3b4);
5-Formyl-1-(3-(1-piperidinyl)phenyl)benzimidazole O-isopropyl oxime (compound 3c);
5-Formyl-1-(3-(1-piperidinyl)phenyl)benzimidazole O-methyl oxime (compound 3d);
5-Acetyl-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazole oxime (compound 3e1);
5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenylbenzimidazole oxime (compound 3e2);
5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenylbenzimidazole O-ethyl oxime (compound 3f1);
5-Acetyl-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole O-ethyl oxime (compound 3f2);
5-Acetyl-1-(3-(1-pyrrolidinylmethyl)phenyl)benzimidazole O-ethyl oxime (compound 3f3);
5-Acetyl-1-(3-(4-methylhomopiperazin-1-yl)benzimidazole O-ethyl oxime (compound 3f4);
5-Acetyl-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole O-ethyl oxime (compound 3f5);
5-Acetyl-1-(3-(1-piperidinyl)phenyl)benzimidazole O-ethyl oxime (compound 3f6);
5-Acetyl-1-(3-(1-methyl-3-piperidinyl)phenyl)benzimidazole O-ethyl oxime (compound 3f7);
5-Acetyl-1-(3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl)benzimidazole O-ethyl oxime (compound 3f8);
5-Acetyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole O-isopropyl oxime (compound 3g1);
5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazole O-isopropyl oxime (compound 3g2);
5-Acetyl-1-(3-(4-acetylpiperazin-1-yl)phenyl)benzimidazole O-isopropyl oxime (compound 3g3);
5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazole O-t-butyl oxime (compound 3h);
5-(3-Furanyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound 3i1);
5-(3-Furanyl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (compound 3i2);
5-(3-Furanyl)-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazole (compound 3i3);
5-(3-Furanyl)-1-(3-(4-(diethylcarboxamidomethyl)piperazin-1-yl)phenyl)benzimidazole (compound 3i4);
5-Phenyl-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound 3j1):
5-Phenyl-1-(3-(1-methylpiperidin-3-yl)phenyl) benzimidazole (compound 3j2):
5-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-1-(3-(1-methylpiperidin-3-yl)phenyl)-benzimidazole (compound 3k);
5-t-Butyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (compound 3l);
5-(Ethoxycarbonyl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (compound 4a1);
5-(Ethoxycarbonyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound 4a2);
5-(Ethoxycarbonyl)-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazole (compound 4a3);
5-(Ethoxycarbonyl)-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazole (compound 4a4);
5-(Ethoxycarbonyl)-1-(3-(4-(methoxycarbonylmethyl)piperazin-1-yl)phenyl)-benzimidazole (compound 4a5);
5-(Ethoxycarbonyl)-1-(3-(4-(ethoxycarbonylmethyl)piperazin-1-yl)phenyl)-benzimidazole (compound 4a6);
5-(2-(Ethoxycarbonyl)ethenyl)-1-(3-(1-piperidyl)phenyl)benzimidazole (compound 4b1);
5-(2-(Ethoxycarbonyl)ethenyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound 4b2);
5-(2-(Ethoxycarbonyl)ethenyl)-1-(3-(4-morfolinyl)phenyl)benzimidazole (compound 4b3);
5-(2-(Methoxycarbonyl)ethenyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound 4c1);
5-(2-(Methoxycarbonyl)ethenyl)-1-(3-(4-morfolinyl)phenyl)benzimidazole (compound 4c2);
5-(Methoxycarbonyl)-1-(3-(1-acetylpiperazin-3-yl)phenyl)benzimidazole (compound 4d1);
5-(Methoxycarbonyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound 4d2);
4-(Methoxycarbonyl)-1-(3-(4-methoxycarbonylmethyl)piperazin-1-yl)benzimidazole (compound 4d3);
5-(Methoxycarbonyl)-1-(3-(4-(diethylcarboxamidemethyl)piperazin-1-yl)phenyl)-benzimidazole (compound 4d4);
5-(Methoxycarbonyl)-1-(3-(4-morfolinyl)phenyl)benzimidazole (compound 4d5);
5-(i-Propyloxycarbonyl)-1-(3-(1-piperidinyl)phenyl)benzimidazole (compound 4e1);
5-(i-Propyloxycarbonyl)-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole (compound 4e2);
5-(i-Propyloxycarbonyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound 4e3);
5-(i-Propyloxycarbonyl)-1-(3-(4-morfolinyl)phenyl)benzimidazole (compound 4e4);
5-(Cyclopropylmethyloxycarbonyl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (compound 4f);
5-(Benzyloxycarbonyl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (compound 4g);
5-(3-Picolyloxycarbonyl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (compound 4h);
5-(2-((Dimethylamino)ethyl)oxycarbonyl)-1-(3-(1-acetylpiperazin-4-yl)phenyl)-benzimidazole (compound 4i);
5-((2-(Dimethylamino)ethyl)oxycarbonyl)-1-(3-(4-(ethoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole (compound 4j);
5-((N,N-Diethylcarboxamido)methyloxycarbonyl)-1-(3-(4-ethoxycarbonylmethyl)-piperazin-1-yl)phenyl)benzimidazole (compound 4k1);
5-((N,N-diethylcarboxamido)-methyloxycarbonyl)-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazole (compound 4k2);
5-(Methoxycarbonylmethyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound 4l1);
5-(Ethoxycarbonylmethyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound 4l2);
5-(Methoxycarbonyl)-1-(3-(4-morfolinyl)phenyl)benzimidazole (compound 4l3);
5-(Ethoxycarbonyl)-1-(3-(4-morfolinyl)phenyl)benzimidazole (compound 4l4);
5-((1-Methylpyrrolidin-2-yl)methoxycarbonyl)-1-(3-(4-(ethoxycarbonylmethyl)-piperazin-1-yl)phenyl)benzimidazole (compound 4m);
5-Acetyl-1-(3-(1-methyl-4-piperidyloxycarbonyl)phenyl)benzimidazole O-isopropyl oxime (compound 5a1);
5-Acetyl-1-(3-(1-methyl-3-piperidyloxycarbonyl)phenyl)benzimidazole O-i-propyl oxime (compound 5a2);
5-Acetyl-1-(3-(2-picolyloxycarbonyl)phenyl)benzimidazole O-i-propyl oxime (compound 5a3);
5-Acetyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole O-(ethoxycarbonyl-methyl) oxime (compound 5b1);
5-Acetyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole O-(methoxycarbonylmethyl) oxime (compound 5b2);
5-Acetyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole O-(methoxycarbonyl-(dimethyl)methyl) oxime (compound 5b3);
5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazole O-(methoxy-carbonylmethyl) oxime (compound 5c1);
5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazol O-(ethoxy-carbonylmethyl) oxime (compound 5c2);
5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazole O -(ethoxy-carbonyl(dimethyl)methyl) oxime (compound 5c3);
5-Acetyl-1-(3-(4-(ethoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole oxime (compound 5d1);
5-Acetyl-1-(3-(4-(ethoxycarbonylmethyl)piperidin-1-yl)phenyl)benzimidazole O-ethyl oxime (compound 5d2);
5-Acetyl-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazole O-(methoxycarbonyl-(dimethyl)methyl) oxime (compound 5e1);
5-Acetyl-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazole O-(methoxycarbonyl-methyl) oxime (compound 5e2);
5-Acetyl-1-(3-(4-morfolinyl)phenyl)benzimidazole-O(methoxycarbonylmethyl) oxime (compound 5e3);
5-Acetyl-1-(3-(4-(methoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole O-i-propyl oxime (compound 5f1);
5-acetyl-1-(3-(4-(2,2-bis(ethoxycarbonyl)ethenyl)piperazin-1-yl)phenyl)benzimidazole O-i-propyl oxime (compound 5f2);
5-Formyl-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole O-(methoxycarbonyl-(dimethyl)methyl) oxime (compound 5g1);
5-Formyl-1-(3-(4-morfolinyl)phenyl)benzimidazole O-(methoxycarbonyl)dimethyl)-methyl) oxime (compound 5g2);
5-(5-Isoxazolyl)-1-(3-(methoxycarbonyl)phenyl)benzimidazole (compound 6a1);
5-(5-Isoxazolyl)-1-(3-ethoxycarbonyl)phenyl benzimidazole (compound 6a2);
1-(3-Ethoxycarbonyl)phenyl-5-phenylbenzimidazole (compound 6b1);
5-Phenyl-1-(3-(4-ethoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole (compound 6b2);
5-Phenyl-1-(3-(2-picolyloxycarbonyl)phenyl)benzimidazole (compound 6b3);
5-Phenyl-1-(3-(3-picolyloxycarbonyl)phenyl)benzimidazole (compound 6b4);
5-Phenyl-1-(3-(1-methylpiperid-3-yloxycarbonyl)phenyl)benzimidazole (compound 6b5);
5-Phenyl-1-(3-((1-methylpiperid-4-yl)oxycarbonyl)phenyl)benzimidazole (compound 6b6);
5-(3-furanyl)-1-(3-(ethoxycarbonyl)phenyl)benzimidazole (compound 6c1);
5-(3-Tetrahydrofuranyl)-1-(3-(ethoxycarbonyl)phenyl)benzimidazole (compound 6c2);
5-(3-Furanyl)-1-(3-(4-(ethoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole (compound 6C3);
5-(3-Furanyl)-1-(3-(4-(t-butoxycarbonyl)piperazin-1-yl)phenyl)benzimidazole (compound 6C4);
5-(3-Furanyl)-1-(3-(4-(methoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole (compound 6c5);
5-(3-Furanyl)-1-(3-(4-(2,2-bis(ethoxycarbonyl)ethenyl)piperazin-1-yl)phenyl)-benzimidazole (compound 6c6);
5-(3-Furanyl)-1-(3-(4-(2-(methoxycarbonyl)ethenyl)piperazin-1-yl)phenyl)-benzimidazole (compound 6C7);
5-(3-Furanyl)-1-(3-(2-(dimethylamino)ethyloxycarbonyl)phenyl)benzimidazole (compound 6c8);
5-Acetyl-1-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]-benzimidazole (compound 7); or
5-Acetyl-1-[3-(1-methylpiperidin-3-yl)phenyl]-benzimidazole (compound 9);
or a pharmaceutically acceptable salt thereof, or an oxide thereof.
Definition of Substituents
In the context of this invention halogen represents fluorine, chlorine, bromine and iodine.
In the context of this invention alkyl designates a straight chain or a branched chain containing of from one to eight carbon atoms (C1-C8-alkyl), including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl, or a cyclic alkyl containing of from three to seven carbon atoms (C3-C7 cycloalkyl), including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In a preferred embodiment of this invention alkyl represents a C1-C4 alkyl, preferably a C1-3-alkyl, most preferred methyl, ethyl, propyl, isopropyl or t-butyl.
In the context of this invention alkenyl designates a group containing of from two to six carbon atoms (C2-C6 alkenyl), including at least one double bond. The chain may be straight or branched. In a preferred embodiment, the alkenyl group is ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, or 3-butenyl.
In the context of this invention alkynyl designates a group containing of from two to six carbon atoms (C2-C6 alkynyl), including at least one triple bond. The chain may be straight or branched. In a preferred embodiment, the alkenyl group is ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, or 3-butynyl.
In the context of this invention amino represents NH2, NH-alkyl, or N-(alkyl)2, wherein alkyl is as defined above.
In the context of this invention cycloalkyl-alkyl designates a cycloalkyl as defined above which is attached to an alkyl as also defined above, e.g. cyclopropylmethyl.
The alifatic cyclic rings formed by Rxe2x80x2 and Rxe2x80x3 or Rxe2x80x3  and Rxe2x80x2xe2x80x3 includes but are not limited to piperidinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, hexahydropyrimidinyl, pyrrolidinyl, homopiperazinyl, morpholinyl, isoxazolidinyl, oxazolindinyl, piperazinyl, perhydroazepinyl, and perhydrooxazepinyl.
In the context of this invention aryl designates an aromatic hydrocarbon, such as phenyl or naphthyl.
In the context of this invention a monocyclic heteroaryl designates a 5- or 6-membered heterocyclic monocyclic group. Preferred monocyclic heteroaryl group includes oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, and 4-pyrazolyl.
In the context of this invention 5- or 6-membered ring containing at least one heteroatom includes but are not limited to furanyl, tetrahydrofuranyl, pyrrolyl, pyrrolidyl, imidazolyl, oxadiazolyl, pyridyl, thienyl, isooxazolyl, pyrimidyl, pyrazole,
In the context of this invention alkyl-oxy (alkoxy) designates an alkyl-Oxe2x80x94 where alkyl is as defined above.
In the context of this invention alkyl-oxycarbonyl (alkoxycarbonyl) designates an alkyl-Oxe2x80x94COxe2x80x94 where alkyl is as defined above.
Steric Isomers
Some of the chemical compounds of the present invention exist in (+) and (xe2x88x92) forms as well as in racemic forms.
Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof, with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optical active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallisation of d- or l- (tartrates, mandelates, or camphorsulphonate) salts for example.
The chemical compounds of the present invention may also be resolved by the formation of diastereomeric amides by reaction of the chemical compounds of the present invention with an optically active activated carboxylic acid such as that derived from (+) or (xe2x88x92) phenylalanine, (+) or (xe2x88x92) phenylglycine, (+) or (xe2x88x92) camphanic acid or by the formation of diastereomeric carbamates by reaction of the chemical compound of the present invention with an optically active chloroformate or the like.
Additional methods for the resolving the optical isomers are known in the art. Such methods include those described by Jaques J, Collet A, and Wilen S in xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, New York (1981).
Moreover, being oximes, the chemical compounds of the invention may exist in two forms, syn- and anti-form (Z- and E-form), depending on the arrangement of the substituents around the xe2x80x94Cxe2x95x90Nxe2x80x94 double bond. A chemical compound of the present invention may thus be the syn- or the anti-form (Z- and E-form), or it may be a mixture hereof.
Pharmaceutically Acceptable Salts
The novel benzimidazole derivatives of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts.
Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as the hydrochloride, hydrobromide, phosphate, nitrate, perchlorate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate, benzenesulfonate, methanesulfonate, stearate, succinate, glutamate, glycollate, toluene-p-sulphonate, formate, malonate, naphthalene-2-sulphonate, salicylate and the acetate. Such salts are formed by procedures well known in the art.
Other acids such as oxalic acid, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt.
Metal salts of a chemical compound of the invention includes alkali metal salts, such as the sodium salt, of a chemical compound of the invention containing a carboxy group.
The chemical compound of the invention may be provided in solved or dissolved form together with a pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solved forms are considered equivalent to dissolved forms for the purposes of this invention.
Pharmaceutical Compositions
In another aspect the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the chemical compound of the invention. While a chemical compound of the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt in a pharmaceutical composition together with one or more excipients, carriers and/or diluents.
In a preferred embodiment, the invention provides pharmaceutical compositions comprising the chemical compound of the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Pharmaceutical compositions those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cuntaneous and intravenous) administration, or in a form suitable for administration by inhalation or insufflation.
The chemical compound of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Compositions containing ten (10) milligrams of active ingredient or, more broadly, 0.1 to one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
The chemical compound of the present invention can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a chemical compound of the invention or a pharmaceutically acceptable salt of a chemical compound of the invention.
For preparing pharmaceutical compositions from a chemical compound of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.
In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term xe2x80x9cpreparationxe2x80x9d is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
The chemical compound according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
For topical administration to the epidermis the chemical compound according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
Compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The compositions may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump.
Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.
Alternatively the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
When desired, compositions adapted to give sustained release of the active ingredient may be employed.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
Biological Activity and Methods of Treatment
4-aminobytyric acid (GABA) is the major inhibitory neurotransmitter which has been shown to act throughout both the central and peripheral nervous system. At present two types of GABA receptors are known, the GABAA and the GABAB receptors. Recent molecular biology has demonstrated that the GABAA receptors can be subdivided into numerous subreceptors consistant with the selective and or partial pharmacological effects observed with certain benzodiazepine receptor ligands as opposed to the unselective effects observed for the classical benzodiazepine receptor ligands such as for example diazepam.
Activation of GABA receptors leads to alternations in membrane potential (hyperpolarization). The GABAA receptors are associated with chloride influx through its associated and integrated chloride channel, whereas GABAB receptor activation indirectly alters potassium and calcium channels as well as modifies second messenger production. The GABAA recognition sites can be activated by GABA, muscimol, and isoguvacine for example, but not by GABAB agonists such as for example baclofen. The modulatory GABAA recognition site at the benzodiazepine receptor sites can be selectively radiolabelled with 3H-flunitrazepam.
The affinity of various potential ligands for the benzodiazepine receptor sites can thus be evaluated by estimating the ability of test compounds to displace 3H-flunitrazepam.
The compounds of the present invention may be useful for the treatment of disorders or diseases of a living animal body due to their modulatory effect on the benzodiazepine recognition site of the GABAA receptor complex. This property make the compounds of this invention extremely useful as muscle relaxants and in the treatment of convulsions, anxiety, sleep disorders, anaestesia, memory disorders as well as other disorders sensitive to modulation of the GABAA receptor.
Accordingly, the compounds of the present invention may be administered to a subject, including a human, in need of treatment, alleviation, or elimination of a disorder or disease associated with GABAA receptors. This includes especially convulsions, anxiety, sleep disorders, anaestesia, and memory disorders.
It is at present contemplated that a suitable dosage range is of from about 0.01 to about 100 mg per day, more preferred of from about 0.1 to about 50 mg per day, most prefferred of from about 0.1 to about 30 mg per day, dependent, however, upon the exact mode of administration, the form in which it is administered, the indication towards which the administration is directed, the subject involved and the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.
Methods of Preparation
The novel benzimidazole derivatives of the invention may be prepared by conventional methods of chemical synthesis, e.g. those described in the working examples. The starting materials for the processes described in the present application are known or may readily be prepared by conventional methods from commercially available chemicals.
The end products of the reactions described herein may be isolated by conventional techniques, e.g. by extraction, crystallisation, distillation, chromatography, etc.